Synthetic mimicry of protein binding sites through structure-based design and computational optimization

• Applicant: Professorin Dr. Jutta Eichler
• Co-Applicant: Dr. Julia Shifman
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2008 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 93101942

Molecules capable of mimicking protein binding and/or functional sites present useful tools for a range of biomedical applications, including the inhibition of protein-ligand interactions. Mimetics of large and sequentially discontinuous protein binding sites can presently be generated through structure-based design and chemical synthesis. The goal of computational protein design, on the other hand, is to improve protein binding affinity and/or specificity by predicting appropriate mutations at protein-protein interfaces. In this project, we will explore the potential synergism resulting from combining the above two strategies by (i) designing and generating synthetic mimetics of a conformationally defined protein binding site, and (ii) optimizing these molecules, regarding their affinities to the protein ligand, through computational design. The interaction of the synaptic enzyme acetylcholinesterase (AChE) with its inhibitor fasciculin-2 (FAS) will serve as a model for this study, since the structure and function of this complex is well understood. Assembled peptides mimicking the discontinuous binding site of AChE for FAS will be synthesized, functionally evaluated, and computationally optimized regarding their affinities to FAS. The results are expected to further enhance the scope and quality of structure-based and computational strategies for the design of inhibitors of molecular interactions involving large protein-protein interfaces.

• DFG Programme: Research Grants
• International Connection: Israel